Many aromatic sulfonylureas of Formula I ##STR1## wherein R is a monocyclic or bicyclic aryl radical and R.sup.1 is an organic radical, are well known in the art. Certain of these compounds are known to have hypoglycemic activities, and have been used medicinally as such agents. In addition, sulfonylureas have been taught to have herbicidal and antimycotic activities. General reviews of compounds of this structural type are taught by Kurzer, Chemical Reviews, 50:1 (1952) and C. R. Kahn and Y. Shechter, Goodman and Gilman's, The Pharmacological Basis of Therapeutics, (Gilman, et al., 8th ed. 1990) 1484-1487.
Some diarylsulfonylureas, including bicyclic aromatic sulfonylureas, have been reported as being active antitumor agents. e.g., U.S. Pat. No. 4,845,128 of Harper, et al. (1989); U.S. Pat. No. 5,110,830 of Harper, et al., issued May 5, 1992; U.S. Pat. No. 5,116,874 of G. A. Poore, issued May 26, 1992; European Patent Publication 0467613 (published Jan. 22, 1992); Grindey, et al., American Association of Cancer Research, 27:277 (1986); and Houghton, et al., Cancer Chemotherapy and Pharmacology, 25:84-88 (1989).
One commonly used synthesis for the preparation of the sulfonylureas of Formula I involves reacting an aryl sulfonamide of Formula II ##STR2## with an isocyanate of Formula III ##STR3## wherein R and R.sup.1 are as defined supra.
In many cases the required sulfonamide is not commercially available and must be synthesized. Such compounds are routinely prepared by synthesizing the corresponding sulfonyl chloride derivative, followed by ammonolysis with ammonium hydroxide or ammonia.
Several methods of synthesizing sulfonyl chlorides are taught in the art. Shah, et al., Journal of Medicinal Chemistry, 12:938 (1969) describe a procedure for preparing sulfonyl chlorides known as the Meerwein Procedure. The Meerwein Procedure involves diazotization of an aniline, followed by reaction with a solution of cupric chloride, concentrated hydrochloric acid, and sulfur dioxide in glacial acetic acid.
Kittila teaches that an N,N-dimethylformamide-sulfuryl chloride adduct reacts with anisole to form paramethoxybenzene sulfonyl chloride. Dimethylformamide Chemical Uses, E. I. DuPont DeNemour and Co., 76, 77 (1967). Two methods for synthesizing bicyclic aromatic sulfonyl chlorides are described by Breuer and co-workers in Chimie Therapeutique, 659 (1979). One method involves a high temperature sulfonation of the bicyclic aromatic compound using hydrogen sulfate, followed by chlorination of the intermediate sulfonic acid. The second method teaches a low temperature chlorosulfonation employing chlorosulfonic acid to both sulfonate and chlorinate.
One synthetic route described by others utilizes the diazonium salt of 3-amino-4-(.beta.-chloroethyl)benzene sulfonamide to directly produce dihydrobenzofuran-6-sulfonamide without forming the sulfonyl chloride intermediate. Breuer, et al., Chimie Therapeutique, 659 (1979)
A process described by J. A. Aikins and E. V. P. Tao teaches the reaction of an oxygen-containing bicyclic aromatic compound with a Vilsmeier reagent of Formula IV ##STR4## to produce sulfonyl chlorides. J. A. Aikins and E. V. P. Tao, European Patent Publication 254,577, published Jan. 27, 1988.
The major drawback with all of these methods for producing bicyclic aromatic sulfonyl chlorides and bicyclic aromatic sulfonamides is that they produce relatively low yields of useful product. The present invention describes a process for the high efficiency synthesis of these sulfonyl halides and sulfonamides.